5-alkylmercapto-2-heterocyclic aldehydes and ketones



nited States Patent 7 2,746,973 Patented May 22, 1956S-ALKYLMERCAPTO-Z-HETEROCYCLIC ALDE- HYDES AND KETONES No Drawing.Application May 27, 1955, Serial No. 511,774

6 Claims. (Cl. 260-3325) This invention relates to a process forpreparing alkylmercapto-2-heterocyclic aldehydes and ketones. Moreparticularly, the invention is concerned with a process for preparingalkyl (S-alkylmercapto-Z-thienyl) ketones, alkyl(5-alkylmercapto-2-furyl) ketones, 5-alkyLmercapto-Z-thiophenecarboxaldehydes andS-alkylmercapto-Z-furaldehydes. The invention is further directed to theketones and aldehydes prepared.

The present application is a continuation-in-part application of ourcopending case Serial No. 387,313, filed October 20, 1953, nowabandoned, which is in turn a continuation-in-part of our parent caseSerial No. 298,843, filed July 14, 1952, now abandoned; and is in part acontinuation of the copending applications of Algird Kreuchunas SerialNos. 304,211, now abandoned, and 309,370, filed August 13, 1952, andSeptember 12, 1952, respectively.

The 5-alkylmercapto-2-heterocyclic aldehydes and ketones of ourinvention are represented by the general formula RSUO 0 R In thisformula R represents hydrogen or lower alkyl, R represents a lower alkylradical and Z represents oxygen or sulfur. By lower alkyl we mean analkyl radical having not more than 6 carbon atoms.

The compounds of Formula 1 are prepared in accordance with the presentinvention by mixing a compound of the formula XUC o R 3. RSM

described in J. Am. Chem.

The S-haIo-Z-thiophenecarboxalkyl mercaptide, the alkali metal being onehaving an atomic number of at least 11 but no greater than 19. Thepreferred solvents for the alkali metal alkyl mercaptide are the loweraliphatic alcohols such as, for example, methanol, ethanol, isopropanoland n-butanol.

The desired product represented by Formula 1 is isolated from thereaction mixture by pouring the mixture into water. The product, whichseparates, is then collected. It can be purified by distillation orcrystallization.

Illustrative of the ketones prepared according to the process of ourinvention are:

Ethyl (5-ethylmercapto-2-thienyl) ketone Methyl(5-n-butylmercapto-Z-thienyl) ketone Amyl(5-isopropylmercapto-Z-thienyl) ketone Hexyl(5-methylmercapto-2-thienyl) ketone n-Propyl(5-n-hexylmercapto-2-thienyl) ketone Isopropyl(5-isopropylmercapto-2-thieny1) ketone n-Butyl(5-methylmercapto-2-thienyl) ketone n-Butyl (S-butylmercapto-2-thienyl)ketone Methyl (5-ethylmercapto-2-furyl) ketone Ethyl(S-hexylmercapto-Z-furyl) ketone Ethyl (5-n-propylmercapto-2-furyl)ketone n-Propyl (5-ethylmercapto-2-furyl) ketone Isopropyl(5-isobutylmercapto-Z-furyl) ketone n-Propyl (S-n-amylmercapto-Z-furyl)ketone n-Butyl (S-methylrnercapto-Z-furyl) ketone5-ethylmercapto-2-thiophenecarboxaldehyde5-n-butylmercapto-2-thiophenecarboxaldehydeS-isoamylmercapto-Z-thiophenecarboxaldehydeS-n-hexylmercapto-Z-thiophenecarboxaldehyde5-isopropy1mercapto-2-furaldehyde 5-ter-amylmercapto-2-furaldehydeS-n-hexylmercapto-2-furaldehyde The compounds of the present inventionare useful in the preparation of other organic compounds and findparticular use as intermediates in the preparation of such synflleticantibiotics as:

(dl) threo 1 (5 methylsulfonyl 2 furyl) 2 (alpha, alphadichloroacetamido) 1,3 propanediol,

(dl) threo 1 (5 ethylsulfonyl 2 furyl) 2 (alpha,

alpha dichloroacetamido)1,3 propanediol,

(dl) threo 1 (5 n propylsulfonyl 2 furyl) 2 (alpha, alphadichloroacetamido) 1,3 propanediol,

(dl) threo 1 (5 methylsulfonyl 2 thienyl) 2 (alpha, alphadichloroacetamido) 1,3 propanediol,

(dl) threo 1 (5 ethylsulfonyl 2 thienyl) 2 (alpha, alphadichloroacetamido) 1,3 propanediol,

(dl) threo 1 (5 n propylsulfonyl 2 thienyl) 2 (alpha, alphadichloroacetamido) 1,3 propanediol.

The conversion of compounds of the present invention to the biologicallyactive 1-(5-alkylsulfonyl2-thienyl)-2- amido-1,3-propanediol is fullydescribed and claimed in the copending application of Algird Kreuchunas,Serial No. 304,211, filed August 13, 1952.

In brief, the synthesis of Kreuchunas application, Serial No. 304,211,comprises oxidizing a methyl (S-alkylmercapto-2-thienyl) ketone of ourinvention to a methyl (5- alkylsulfonyl-Z-thienyl) ketone using hydrogenperoxide.

' The methyl (5-alkylsulfonyl-2-thienyl) ketone is brominated and theresulting bromomethyl (5-alkylsulfonyl-2- thienyl) ketone is mixed inethylidene dichloride with hexamethylenetetramine to obtainN-(5-alkylsulfonyl-2- thenoylmethyl hexamethylenetetraminium bromide.The tetraminium salt is converted to (hydroxymethylamino) methyl(5-alkylsulfonyl-Z-thienyl) ketone sulfite using sulfur dioxide andwater. The sulfite is converted to N-(5- alkylsulfonyl-Z-thenoyl)methylamine hydrochloride using hydrochloric acid, and the hydrochloricis in turn acylated. The resulting amide derivative is subjected to analdol type of condensation (hydroxymethylation) to yield a compound ofthe formula The carbonyl group of the above compound is reduced to givethe desired biologically active product using sodium borohydride or theMeerwein-Ponndorf-Verley method.

The conversion of the alkyl (5-alkylmercapto-2-furyl) ketones of ourinvention to pharmaceutically active products is fully described andclaimed in the copending Kreuchunas application, Serial No. 309,370,filed September 12, 1952. The conversion is similar to the one alreadydescribed for the thienyl derivatives.

Additionally, the aldehydes and ketones of this invention are useful ascorrosion inhibitors.

The acid corrosion of steel, say, in the presence of a mineral acid suchas 5% sulfuric acid, is substantially inhibited when a minor quantity ofa compound of the invention is added to the acid system. Uninhibitedacidsteel systems corrode at least 2% times faster than systemscontaining one or more of our novel compounds.

In order to better understand our invention reference should be had tothe following illustrative examples:

EXAMPLE 1 Preparation of methyl (S-methylmercapto-Z-thienyl) ketoneOHBSUO o Ha T o a solution of 39 g. of potassium hydroxide in 500 ml. ofethanol at 25 C. there is added over a period of thirty minutes 28.3 g.of gaseous methyl mercaptan. 120 g. of methyl (-bromo-2-thienyl) ketoneis then added in one portion. The reaction mixture is stirred andrefluxed for a period of three hours. The mixture is cooled and pouredinto 3 l. of water. A yellow solid separates consisting essentially ofmethyl (S-methylmercapto-2-thienyl) ketone. It is collected byfiltration and dried. The yield of product is 100 g., M. P. 52-53 C. Ifdesired, the material may be recrystallized from hexane.

Anal.Calcd. for CrHaOSz: C, 48.81; H, 4.68; S, 37.22. Found: C, 49.12;H, 4.75; S, 37.16.

EXAMPLE 2 Preparation of methyl (S-ethylrnercapto-Z-thienyl) ketone Asolution of sodium ethyl mercaptide is prepared by dissolving 25.3 g. ofsodium metal in 1 liter of ethanol. To this ethanolic solution at C.there is added slowly 68.2 g. of ethyl mercaptan followed by 205 g. ofmethyl (5-bromo-2-thienyl) ketone in one portion. The resulting mixtureis stirred and refluxed for a period of ten hours. The reaction mixtureis poured into 4 l. of Water. The low melting solid which separates ismethyl (S-ethylmercapto-Z-thienyl) ketone. It is collected byfiltration, Washed with 200 ml. of water and dried to give a yield of165 g.

EXAMPLE 3 Preparation of ethyl (S-methylmercapto-Z-thienyl) ketone CHgSUS u-COCHEB To a solution of 39 g. of potassium hydroxide in 500 ml. ofethanol at 25 C..there is added over a period of EXAMPLE 4 Preparationof n-propyl (S-ethylmercapto-Z-thienyl) ketone mmsUooomornom To asolution of 39 g. of potassium hydroxide in 500 ml. of ethanol at 25 C.there are added slowly 36.6 g. of ethyl mercaptan, followed by a singleportion addition of 103.7 g. of n-propyl (5-chloro-2-thienyl) ketone.The reaction mixture is refluxed for a period of ten hours. It is thencooled and poured into 3 1. of water. The desired product comprisingn-propyl (S-ethylmercapto-Z- thienyl) ketone, is extracted with benzeneand distilled.

EXAMPLE 5 Preparation of methyl (5-methylme rcapto-Z-furyl) ketone CHaSL 0 LC 0 CH:

To a solution of 39 g. of potassium hydroxide in 500 ml. of ethanol at25 C. there are added in sequence 28.3 g. of gaseous methyl mercaptanand 104 g. of methyl (5-bromo-2-furyl) ketone. The reaction mixture isrefluxed for a period of three hours, cooled and poured into 3 l. ofwater. The resulting methyl (S-methylmercapto-Z-furyl) ketone isextracted with benzene and distilled. An eighty gram yield is realized.

EXAMPLE 6 Preparation of isopropyl(5-is0pr0pylmercapt0-2-furyl) ketone Asolution of sodium isopropyl mercaptide is prepared by dissolving 25.3g. of sodium metal in 1 liter of methanol, cooling to a temperature of25 C. and adding slowly 83.6 g. of isopropyl mercaptan. To this mixture,

there is added in one portion 217 g. of isopropyl (S-bromo- 2-furyl).The resulting mixture is refluxed for a period of three hours, cooledand poured into 4 liters of water. The isopropyl(S-isopropylmercapto-Z-furyl) ketone thus produced is extracted withbenzene, dried, and distilled. The yield is g.

EXAMPLE 7 Preparation of n-propyl(5-n-pr0pylmercapt0-2-furyl) ketone Toa solution of 39 g. of potassium hydroxide in 500 ml. of ethanol at 25C. there is added 44.8 g. of n-propyl mercaptan. Next, 95. g. ofn-propyl (S-chloro-Z-furyl) ketone isadded in one portion. The resultingmixture is refluxed for a period of twelve hours, cooled and poured into3 l. of water. The product, n-propyl (S-n-propylmercapto-2-furyl)ketone, is extracted with benzene, dried and distilled. The yield of thedesired ketone is 96 g.

EXAMPLE 8 S-methylmercapto-Z-thicphenecarboxaldehyde omsUono is purifiedby distilling under reduced pressure.

EXAMPLE 9 5-isopropylmercapt0-2-thi0phenecarboxaldehyde This compound isprepared exactly as in Example 8 except 80 g. of isopropyl mercaptan isadded by a drop ping funnel instead of bubbling in gaseous methylmercaptan. The product, having the structure (onmonsUono is isolated andpurified in the same manner as in Example 8.

EXAMPLE 10 5-n-propylmercapto-2-thiophenecarboxaldehyde This compound isprepared, isolated and purified as in 'Example 8 except 80 g. ofn-propyl mercaptan is added by a dropping funnel instead of bubbling ingaseous methyl mercaptan. The product has the structure CHaOHnCHzS-U-CHOEXAMPLE l1 5 -methylmercapto-2-furaldehyde To a solution of 56.1 g. ofpotassium hydroxide and 500 ml. of ethanol at 25 C., there are added insequence 48 g. of gaseous methyl mercaptan and 175 g. of S-bromo-2-furaldehyde. The reaction mixture is refluxed for a period of 3 hours.The potassium bromide is filtered off and the ethanol solution vacuumconcentrated. The product, having the structure 0 Has [1C H O 0 ispurified by distilling under reduced pressure.

EXAMPLE 12 5-ethylmercapt0-2-furaldehyde This compound is prepared,isolated and purified in the manner described in Example 11 except g. ofethyl mercaptan is added in place of the methyl mercaptan. The producthas the structure omomsU-ono EXAMPLE 13 5 -n-butylmercapto-Z-furaldehydeThis compound is prepared, isolated, and purified as in Example 11except 92. g. of n-butyl mercaptan is added by a dropping funnel insteadof bubbling in the methyl mercaptan. The product has the structure CHaCHaC H2O HISUCHO We claim:

1. A compound of the formula where R is a member of the group consistingof hydrogen and lower alkyl and R is lower alkyl and Z is a member ofthe group consisting of oxygen and sulfur.

2. Methyl (5-methylmercapto-Z-thienyl) ketone.

3. 5-methylmercapto-2-thiophenecarboxaldehyde.

4. S-methylmercapto-2-fura1dehyde.

5. Methyl (5-methylmercapto-2-furyl) ketone.

6. Methyl (5-ethylmercapto-Z-thienyl) ketone.

No references cited.

1. A COMPOUND OF THE FORMULA
 6. METHYL (5-ETHYLMERCAPTO-2-THIENYL)KETONE.